Human IgM antibodies, and diagnostic and therapeutic uses thereof particularly in the central nervous system

Abstract

Antibodies, and particularly human antibodies, are disclosed that demonstrate activity in the treatment of demyelinating diseases as well as other diseases of the central nervous system that are of viral, bacterial or idiopathic origin, including neural dysfunction caused by spinal cord injury. Neuromodulatory agents are set forth that include and comprise a material selected from the group consisting of an antibody capable of binding structures or cells in the central nervous system, a peptide analog, a hapten, active fragments thereof, agonists thereof, mimics thereof, monomers thereof and combinations thereof. The neuromodulatory agent has one or more of the following characteristics: it is capable of inducing remyelination; binding to neural tissue; promoting Ca ++ signaling with oligodendrocytes; and promoting cellular proliferation of glial cells. Amino acid and DNA sequences of exemplary antibodies are disclosed. Methods are described for treating demyelinating diseases, and diseases of the central nervous system of humans and domestic animals, using polyclonal IgM antibodies and human monoclonal antibodies sHIgm22(LYM 22), sHIgm46(LYM46) ebvHIgM MSI19D10, CB2bG8, AKJR4, CB2iE12, CB2iE7, MSI19E5 and MSI10E10, active fragments thereof and the like. The invention also extends to the use of human antibodies, fragments, peptide derivatives and like materials, and their use in diagnostic and therapeutic applications, including screening assays for the discovery of additional antibodies that bind to cells of the nervous system, particularly oligodendrocytes.

1. A pharmaceutical composition comprising an isolated human monoclonal antibody capable of binding oligodendrocytes and capable of inducing remyelination selected from the group consisting of an antibody having a heavy chain sequence comprising the heavy chain variable region sequence of SEQ ID NO:7 and a light chain sequence comprising the light chain variable region sequence of SEQ ID NO:9, IgM monomers thereof, Fab, Fab′, F(ab′) 2  or F(v) fragments thereof, and recombinant antibodies derived therefrom having a heavy chain sequence comprising the heavy chain variable region sequence of SEQ ID NO:7 and a light chain sequence comprising the light chain variable region sequence of SEQ ID NO:9 and a pharmaceutically acceptable carrier, vehicle or diluent. 
     
     
       2. A pharmaceutical composition comprising an isolated antibody capable of binding oligodendrocytes and capable of inducing remyelination having a heavy chain sequence comprising the heavy chain variable region sequence of SEQ ID NO:7 and a light chain sequence comprising the light chain variable region sequence of SEQ ID NO:9 and a pharmaceutically acceptable carrier, vehicle or diluent. 
     
     
       3. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, vehicle, or diluent and an amount of an isolated antibody polypeptide capable of binding oligodendrocytes and capable of inducing remyelination produced by the method of
 (a) introducing a vector comprising a DNA molecule comprising a DNA sequence encoding an antibody polypeptide having a heavy chain sequence comprising the amino acid sequence set out in  FIG. 35  (SEQ ID NO:7) and a light chain sequence comprising the amino acid sequence set out in  FIG. 36  (SEQ ID NO:9) into a suitable host cell; 
 (b) culturing the resulting host cell so as to produce the polypeptide; 
 (c) recovering the polypeptide produced in step (b); and 
 (d) purifying the polypeptide recovered in step (c). 
 
     
     
       4. An isolated antibody capable of binding oligodendrocytes and capable of inducing remyelination and having a heavy and light chain, wherein the heavy chain sequence comprises the amino acid sequence set out in  FIG. 35  (SEQ ID NO:7) and the light chain sequence comprises the amino acid sequence set out in  FIG. 36  (SEQ ID NO:9), or Fab, Fab′, F(ab′) 2  or F(v) fragments thereof capable of binding oligodendrocytes and capable of inducing remyelination. 
     
     
       5. An isolated antibody capable of binding oligodendrocytes and capable of inducing remyelination having a heavy chain and a light chain, wherein the heavy chain sequence comprises the heavy chain variable region sequence as set out in  FIG. 35  (SEQ ID NO:7). 
     
     
       6. An isolated antibody capable of binding oligodendrocytes and capable of inducing remyelination having a heavy chain and a light chain, wherein the light chain sequence comprises the light chain variable region sequence as set out in  FIG. 36  (SEQ ID NO:9). 
     
     
       7. An isolated monoclonal antibody capable of binding oligodendrocytes and capable of inducing remyelination selected from the group consisting of mAb sHIgM22 (LYM 22) antibody (ATCC Accession No. PTA-8671), IgM monomers thereof, Fab, Fab′, F(ab′) 2  or F(v) fragments thereof. 
     
     
       8. A pharmaceutical composition comprising the isolated antibody of  claim 7  and a pharmaceutically acceptable carrier, vehicle or diluent.